Originally published as JCO Early Release 10.1200/JCO.2008.20.9445 on March 16 2009

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Chemotherapy Alone for Laryngeal Preservation—Is It Possible?

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD

Ashok R. Shaha

Head and Neck Service, Memorial Sloan-Kettering Cancer Center, New York, NY

Holsinger et al¹ report the results of a phase II trial testing chemotherapy alone as definitive treatment for preservation of the larynx in selected patients with stages II to IV laryngeal cancer. This study is the first of its kind in the United States, even though the approach has been tried in France by Laccourreye et al^2,3 in patients with T1 to T3N0 glottic cancers. In their study, Holsinger et al were careful to select patients with T2 to T4 cancers of the glottic or supraglottic larynx who could be treated with conservation laryngeal surgery. Using a regimen of cisplatin plus ifosfamide plus paclitaxel (TIP), chemotherapy alone proved successful, with no local or regional failures in 10 patients (32%) demonstrating biopsy-confirmed complete response (CR) out of 31 patients enrolled. These results are important because they underscore the sensitivity of squamous cell cancer of the larynx to cisplatin-based chemotherapy, the potential for chemotherapy as a single-modality treatment option in selected patients with laryngeal cancer, conservation laryngeal surgery as an organ-preserving option for appropriate patients selected by an experienced team, and the importance of a multidisciplinary care team in the evaluation, management, and follow-up of patients with head and neck cancer.

Seven years were required for the accrual of nine patients with T3 or T4, N0 or N1 cancers suitable for conservation laryngeal surgery, in addition to the 22 patients with T2N0 or N1 cancers who were identified as being at high risk for recurrence with altered fractionation radiotherapy, and who were also candidates for conservation laryngeal surgery. These 31 patients, all of whom had excellent performance status, received either three or four cycles of TIP followed by response assessment. All patients achieved either a CR or partial response to TIP. If a CR was determined on the basis of imaging, endoscopic examination, and negative biopsy, additional cycles of TIP were administered (up to a maximum of six cycles), after which patients were rigorously monitored. Patients with less than a biopsy-proven CR underwent appropriate laryngeal surgery, with or without neck dissection and radiation, as indicated.

A high rate of laryngeal preservation was achieved (83%; 95% CI, 65 to 94), significantly better than the rate of 60%, which had been determined—on the basis of previous studies^4,5 of stage III and IV laryngeal cancers treated for organ preservation in patients in whom total laryngectomy would otherwise have been required—sufficient for declaring the treatment a success. Clearly, the bar had been set too low for this patient group, in which stage II disease was predominant, and which was suitable for conservation laryngeal surgery from the outset. The estimated survival outcomes at 5 years were an overall survival of 83% (95% CI, 70 to 98) and a recurrence-free survival (deaths not resulting from study cancer were censored) of 73% (95% CI, 58 to 91), suggesting that the treatment approach was not detrimental.

Standard of care management of laryngeal cancer varies with stage, but an integral goal is preservation of laryngeal function with good voice quality and the ability to swallow without aspirating. For early stage cancers (ie, T1N0 and most T2N0 cancers), these goals are readily achievable with a single modality: surgery (either endoscopic laser surgery or open partial surgery) or radiation therapy. These treatments result in equally high rates of disease control ranging from 80% to nearly 100%, depending on T stage and subsite involvement. The most significant difference is in voice quality, which is generally superior with radiation therapy, the preferred treatment in the United States for most early stage cancers. For some T2 cancers (eg, glottic cancer with impaired vocal cord mobility or subglottic extension, and supraglottic cancer with pre-epiglottic space involvement), there is a need for improved treatment because of an increased risk of failure and the need for subsequent salvage total laryngectomy, even with accelerated radiation fractionation schedules. Rather than considering chemoradiotherapy as an alternative for T2N1, T3, and T4 cancers, Holsinger et al¹ seem to have selected this group for which improved treatment is needed for their experimental treatment approach. Several aspects of the study design and results should be highlighted. First, the authors included supracricoid laryngectomy as conservation laryngeal surgery for patients with T3 and T4 cancers. Supracricoid laryngectomy is quite popular in Europe, especially in France and Italy, as a method of preserving organ function in patients with advanced cancer. However, this is an operation rarely used in the United States as primary surgical therapy; thus, experience is limited, and the outcome is unsatisfactory. Instead, in the United States, most patients with T3 or T4 cancers of the larynx undergo total laryngectomy or concomitant chemoradiotherapy for laryngeal preservation; this situation led to the lengthy duration of this study to accrue nine patients with T3 and T4 larynx cancer. Although the occurrence of histologic CR in a few patients with advanced cancer is intriguing, we strongly caution against the inclusion of patients with T4 cancers (only three patients in this series had T4 cancers) in such an approach. It is noteworthy that another group exploring single-agent chemotherapy in advanced laryngeal cancer found that it was not feasible for patients with T4 cancers.⁶

The results were excellent for the 10 patients with no evidence of recurrent disease who underwent chemotherapy alone. However, six patients underwent total laryngectomy. One could therefore argue against this approach because of the loss of larynx in six patients who otherwise could have undergone a larynx preservation surgical approach at the outset. Holsinger et al¹ describe a comprehensive multidisciplinary approach in the evaluation, decision making, and treatment regarding these patients, including rigorous follow-up with clinical evaluation and videostroboscopic examination every month, and appropriate laryngoscopy, biopsy, and computed tomography imaging every 3 months. It should be recognized that this intense follow-up by a dedicated team is rarely available outside of major referral centers, but it is critical to the success of novel approaches, such as the one reported by Holsinger et al.

It is important to offer the best treatment approach to selected patients so they can avoid total laryngectomy altogether. In the trial by Holsinger et al,¹ after chemotherapy, patients demonstrating clinical CRs and partial responses were offered conservation laryngeal surgery. Whether radiation therapy instead of surgery would have offered similar long-term results is unclear. The excellent local control achieved with chemotherapy alone in selected patients is noteworthy, and it not only underscores the role of chemotherapy in a laryngeal preservation approach, but also suggests that laryngeal cancer is biologically different from hypopharyngeal and oral cavity cancers.

The marked sensitivity to cisplatin of previously untreated squamous cell cancer of the head and neck has been noted since cisplatin first entered clinical testing in the 1970s.^7,8 Rapid tumor regression occurs, sometimes within days of the first dose, and when combined with infusional fluorouracil, high rates of objective response (80% to 90%) and clinical CR (30% to 50%) are observed. Moreover, approximately two thirds of clinical CRs are confirmed pathologic CRs after biopsy. Indeed, the observation that normal larynges were occasionally removed in the early trials of induction chemotherapy administered before surgery provided the rationale for subsequent laryngeal preservation trials, which compared total laryngectomy with treatment with three cycles of induction cisplatin plus fluorouracil followed by radiotherapy.

The association between objective tumor response to two to four cycles of cisplatin-based chemotherapy and a favorable response to subsequent radiation therapy has long been noted. The basis of this association is the similarity of the mechanism of DNA strand breakage caused by alkylating agents and radiation. This crude surrogate biomarker has been used for nearly two decades to select patients for organ preservation (ie, objective responders) and patients for conventional radical surgery (ie, nonresponders) in the treatment of locally advanced laryngeal, hypopharyngeal, and oropharyngeal cancers.^4,5,9-11 It is probable that only a small minority of patients can be cured with single-modality chemotherapy, and we do not have any way of identifying these patients. We have to incorporate other outcome predictors, in addition to observed response, to exploit the full potential of cisplatin-based chemotherapy in selected patients. Potential predictive markers include excision repair cross-complementation group 1 gene expression for cisplatin sensitivity, thymidylate synthase for fluorouracil, and survivin expression for taxanes. The addition of biologics to cytotoxic regimens and associated biomarker testing provides other possibilities for enhancing efficacy and aiding in patient selection.

In summary, Holsinger et al¹ have provided an excellent preliminary report; however, we would caution readers about its practical utility without additional substantiation from other centers. This approach should be considered only in highly selected patients on a protocol basis in institutions in which truly multidisciplinary teams are available, and intensive follow-up with appropriate investigation is possible.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Manuscript writing: Arlene A. Forastiere, Ashok R. Shaha

Final approval of manuscript: Arlene A. Forastiere, Ashok R. Shaha

REFERENCES

1. Holsinger FC, Kies MS, Diaz EM, et al: Durable long-term remission with chemotherapy alone for stage II to IV laryngeal cancer. J Clin Oncol 27:1976–1982, 2009.[Abstract/Free Full Text]

2. Laccourreye O, Brasnu D, Bassot V, et al: Cisplatin-fluorouracil exclusive chemotherapy for T1-T3N0 glottic squamous cell carcinoma complete clinical responders: Five-year results. J Clin Oncol 14:2331–2336, 1996.[Abstract]

3. Laccourreye O, Veivers D, Bassot V, et al: Analysis of local recurrence in patients with selected T1-3N0M0 squamous cell carcinoma of the true vocal cord managed with a platinum-based chemotherapy-alone regimen for cure. Ann Otol Rhinol Laryngol 111:315–321 discussion 321-322, 2002.

4. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer: The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 324:1685–1690, 1991.[Abstract]

5. Forastiere AA, Goepfert H, Maor M, et al: Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 349:2091–2098, 2003.[Abstract/Free Full Text]

6. Worden FP, Wolf G, Eisbruch A, et al: Chemo-selection of patients (pts) for organ preservation in advanced laryngeal cancer: Failure of chemotherapy (CT) as the sole treatment for complete histologic responders (CHR) to neoadjuvant chemotherapy. J Clin Oncol 24:295s; 2006 (suppl) abstr 5560.

7. al-Sarraf M, Kish JA, Ensley JF: The Wayne State University experience with adjuvant chemotherapy of head and neck cancer. Hematol Oncol Clin North Am 5:687–700, 1991.[Medline]

8. Forastiere AA: Randomized trials of induction chemotherapy: A critical review. Hematol Oncol Clin North Am 5:725–736, 1991.[Medline]

9. Urba S, Wolf G, Eisbruch A, et al: Single-cycle induction chemotherapy selects patients with advanced laryngeal cancer for combined chemoradiation: A new treatment paradigm. J Clin Oncol 24:593–598, 2006.[Abstract/Free Full Text]

10. Lefebvre JL, Chevalier D, Luboinski B, et al: Larynx preservation in pyriform sinus cancer: Preliminary results of a European Organization for Research and Treatment of Cancer phase III trial—EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst 88:890–899, 1996.[Abstract/Free Full Text]

11. Calais G, Alfonsi M, Bardet E, et al: Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst 91:2081–2086, 1999.[Abstract/Free Full Text]

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